Attenuation of experimental autoimmune myocarditis by blocking activated T cells through inducible costimulatory molecule pathway

OBJECTIVE: Inducible costimulator (ICOS) is a member of the CD28 family. Although inflammation is an essential pathological feature of myocarditis, the role of ICOS in myocarditis remains unclear. METHODS AND RESULTS: Lewis rats were immunized on day 0 with purified porcine cardiac myosin to establish experimental autoimmune myocarditis (EAM). Flow cytometry was used to examine expression of ICOS on myocardial infiltrating cells. Anti-ICOS antibody or ICOS-immunoglobulin (ICOSIg) was administered intravenously, and rats were killed on day 14 or 21 to study effects of ICOS/ICOS-ligand (ICOSL) pathway blockade during the antigen priming phase (days 0-14) or immune response phase (days 14-21), respectively. The heart weight to body weight ratio was determined, and histological examination and echocardiogram were performed to evaluate the severity of the disease. Cytokine expression in the heart and T cell proliferation against cardiac myosin were analyzed. Flow cytometry revealed that the majority of infiltrating cells, especially CD4-positive cells, expressed ICOS. Blockade of the ICOS/ICOSL pathway during the immune response phase attenuated EAM development. However, blockade of the ICOS/ICOSL pathway during the antigen priming phase did not attenuate and exacerbate EAM. Blockade of T cell activation through ICOS suppressed expression of cytokines including INF-gamma, IL-4, IL-6, IL-10, IL-1 beta, and TNF-alpha and inhibited T cell proliferation in vitro. CONCLUSIONS: Blockade of T cell activation through ICOS during the immune response phase regulates development of EAM, and therefore, ICOS may be an effective target for treating myocarditis.     

Enhancement of poly-adenosine diphosphate-ribosylation in human hepatocellular carcinoma

BACKGROUND: Poly-adenosine diphosphate (ADP)-ribosylation, catalysed by poly(ADP-ribose) polymerase (PARP), is a post-translational modification of nuclear proteins and is involved in a wide range of biological processes including DNA repair, cell proliferation and malignant transformation. Alteration of this reaction in human hepatocellular carcinoma (HCC) is of interest, but has not yet been explored. The aim of this study was to evaluate poly-ADP-ribosylation and to compare the expression of PARP in HCC and adjacent non-tumour tissues. METHODS: Tumorous and adjacent non-tumorous tissues were obtained from five consecutive patients with HCC during surgery for tumour resection. Tissue homogenates were subjected to ADP-ribosylation with [32P]-nicotinamide adenine dinucleotide. The ADP-ribosylated proteins were separated by sodium dodecylsulfate-polyacrylamide gel electrophoresis, followed by autoradiography. Expression of PARP was also evaluated by western blotting. RESULTS: Several proteins were ADP-ribosylated in human HCC tissues. Notably, the radiolabelling of a 116-kDa protein was remarkably greater than that in adjacent non-tumorous tissues (86.5 +/- 35.2 arbitrary units by densitometry vs 12.2 +/- 9.9, mean +/- SD, n = 5, P < 0.02). The radiolabelling of the 116-kDa protein was decreased in the presence of PARP inhibitors in a concentration-dependent manner. Immunoblot analyses revealed that the radiolabelled protein was PARP and that its expression was significantly greater in HCC than in adjacent non-tumorous tissues (333 +/- 204% of non-tumorous tissue, P < 0.05). CONCLUSIONS: We found that poly-ADP-ribosylation and PARP expression were significantly increased in human HCC compared with those in adjacent non-tumorous tissues in surgically obtained specimens.     

Usefulness of left ventricular volume in assessing tetralogy of Fallot for total correction

Ninety-one patients with tetralogy of Fallot underwent intracardiac repair between 1978 and 1981. One patient died from left-sided heart failure. Retrospective analyses of this death revealed a significant decrease of the left ventricular (LV) end-diastolic volume index (EDVI) of 21 ml/m2 (36% of normal). Results of early postoperative hemodynamic studies after total correction of this anomaly suggested that an EDVI of 30 ml/m2 is the minimal requirement for adequate cardiac output postoperatively. Based on these data, 3 patients with decreased LV volume with EDVI of around 30 ml/m2 were challenged with the primary repair with success, although they required atrial pacing and catecholamine support postoperatively to maintain adequate left atrial pressure and cardiac output. From these results, it is recommended that patients with tetralogy of Fallot and an EDVI of 30 ml/m2 or more can be considered as candidates for the primary repair, but that patients with an EDVI of less than 30 ml/m2 should be palliated once by systemic-to-pulmonary arterial shunt procedures. Subsequent total correction should be performed after sufficient LV growth for those patients.     

Nucleolar organizer regions, nuclear DNA content, and proliferative activity in adenocarcinoma of the lung]

The relationship between the quantity of silver-binding nucleolar organizer regions (AgNORs), nuclear DNA content, and proliferative activity was studied in 61 patients with adenocarcinoma of the lung. The proliferative activity of adenocarcinoma was estimated by tumor volume doubling time based on chest X-ray findings. There was a high, inverse correlation between the AgNORs and the tumor doubling time (p less than 0.001, r = -0.815), and the contribution rate was high value (2 = 0.664). However, the AgNORs value was an independent prognostic factor for survival time. A better 5-year survival rate was observed in patients with DNA diploidy than in DNA aneuploidy, but there was no statistical difference between the two groups. There was an inverse correlation between the DNA index and tumor doubling time (p less than 0.05, r = -0.565), but the contribution rate had a low value (r2 = 0.319). These results indicate that the AgNORs value is important in providing an estimate of the proliferative activity of adenocarcinoma.     

Role of the Pharyngeal Branch of the Vagus Nerve in Laryngeal Elevation and UES Pressure During Swallowing in Rabbits

Abstract Elevation of the larynx during swallowing plays an important role in protecting the laryngeal inlet and in the opening of the upper esophageal sphincter (UES). The thyrohyoid (TH) muscle is the most important muscle for laryngeal elevation, and it is thought to be innervated by the thyrohyoid branch. However, in preliminary studies we found that laryngeal elevation was severely disturbed after sectioning of the pharyngeal branch of the vagus nerve (X-ph). In the present study, we examined the role of the X-ph in laryngeal elevation and the contribution of this nerve to UES pressure. Ten male rabbits under anesthesia were used. Sectioning of the X-ph not only abolished the electromyographic activities of the TH and cricopharyngeus (CP) muscles, it also greatly reduced the maximal value of laryngeal elevation during swallowing. On the other hand, sectioning of the hypoglossal nerve, which contains the thyrohyoid branch, produced no appreciable change in the electromyographic activity of either muscle and it reduced the maximal value of the elevation only slightly. These results indicate that the X-ph innervates the TH and CP muscles and suggest that the X-ph plays an important role in elevating the larynx and in regulating the UES pressure in rabbits.